In the United States, more than one million new cancer cases are diagnosed and about half million people die of cancer. The causes of cancer are many and varied, and include genetic predisposition, environmental influences, infectious agents and ageing. These transform normal cells into cancerous ones by derailing a wide spectrum of regulatory and downstream effector pathways. Several essential alterations in cell physiology collectively dictate malignant growth: self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis (Hanahan and Weinberg (2000), Cell 100:57-70).
To date, researchers have been able to identify many genetic alterations believed to underlie tumor development. These genetic alterations include amplification of oncogenes and mutations that result in the loss of tumor suppressor genes. Oncogenes were initially identified as genes carried by viruses that cause transformation of their target cells. A major class of the viral oncogenes have cellular counterparts that are involved in normal cell functions. The cellular genes are called proto-oncogene, and in certain cases their mutation or aberrant in the cell is associated with tumor formation. The generation of a oncogene represents a gain-of-function in which a cellular proto-oncogene is inappropriately activated. This can involve a mutational change in the protein, or constitutive activation, over-expression, or failure to turn off expression at the appropriate time. About 100 oncogenes have been identified. Examples of oncogenes include, but are not limited to, ras, fos, myc, abl, and myb (Ponder (2001), Nature 411:336-341). Tumor suppressor genes, in their wild-type alleles, express proteins that suppress abnormal cellular proliferation. When the gene coding for a tumor suppressor protein is mutated or deleted, the resulting mutant protein or the complete lack of tumor suppressor protein expression may fail to correctly regulate cellular proliferation, and abnormal proliferation may take place, particularly if there is already existing damage to the cellular regulatory mechanism. A number of well-studied human tumors and tumor cell lines have missing or non-functional tumor suppressor genes. Examples of tumor suppressor genes include, but are not limited to, the retinoblastoma susceptibility gene or RB gene, the p53 gene, the deletion in colon carcinoma (DCC) gene and the neurofibromatosis type 1 (NF-1) tumor suppressor gene (Weinberg (1991), Science 254:1138-1146). Loss-of-function or inactivation of tumor suppressor genes may play a central role in the initiation and/or progression of a significant number of human cancers.
The utilization of genome-wide expression profiles to classify tumors, to identify drug targets, to identify diagnostic markers and/or to gain further insights into the consequences of chemotherapeutic treatments could facilitate the design of more efficacious stratagems for treating a variety of cancers. Initial studies utilizing gene expression patterns to identify subtypes of cancer produced rather intriguing results (see Perou et al. (1999), Proc Natl Acad Sci USA 96:9212-9217; Golub et al. (1999), Science 286:531-537; Alizadeh et al. (2000), Nature 403:503-511; Alon et al. (1999), Proc Natl Acad Sci USA 96:6745-6750; and Bittner et al. (2000), Nature 406:536-540; Perou et al. (2000), Nature 406:747-752). Molecular classification of B-cell lymphoma by gene expression profiling elucidated clinically distinct diffuse large-B-cell lymphoma subgroups (see Alizadeh et al., supra). In breast cancer, studies utilizing limited numbers of genes (8,102 genes) have classified tumors into subtypes based on gene expression profiles, and this study indicated a diversity of molecular phenotypes associated with breast tumors (see Perou et al., supra). In addition, the expression profiling has enabled researchers to map tissue-specific expression levels for thousands of genes (Alon et al. (1999), Proc Natl Acad Sci USA 96:6745-6750; Iyer et al. (1999), Science 283:83-87; Khan et al. (1998), Cancer Res 58:5009-5013; Lee et al. (1999), Science 285:1390-1393; Wang et al. (1999), Gene 229:101-108; Whitney et al. (1999), Ann Neurol 46:425-428). Although these studies have demonstrated that expression profiling may be used to produce improvements in diagnosis of human diseases such as cancer, as well as in the development of improved therapeutic strategies, further studies are needed.
Although cancers are diverse and heterogeneous as they are derived from numerous tissues and multiple etiologic factors, it has been suggested that underlying this variability lies a relatively small number of critical events whose convergence is required for the development of any and all cancers (Evan and Vousden (2001), Nature 411:342-348). Accordingly, there exists a need for the comprehensive investigation of the changes in global gene expression levels in many different types of cancers to identify critical molecular markers associated with the development and progression of cancer. There remains a need in the art for materials and methods that permit a more accurate diagnosis of cancer. In addition, there remains a need in the art for methods to treat and methods to identify agents that can effectively treat this disease. The present invention meets these and other needs.